Cumulative Metformin Use and Hepatocellular Carcinoma Risk After HCV SVR : A Multicentre Cohort Study

BACKGROUND: Although sustained virological response (SVR) after hepatitis C virus treatment reduces hepatocellular carcinoma (HCC) incidence, residual risk persists. Metformin has been associated with lower HCC risk, but whether cumulative metformin exposure (CME) lowers post-SVR risk remains unclear. We evaluated whether CME was associated with lower HCC risk after SVR. METHODS: We analysed a multicentre cohort of 1531 patients who achieved SVR after direct-acting antiviral therapy (median follow-up, 75.5 months). Metformin exposure was modelled as a time-updated cumulative variable in start-stop Cox models to control for immortal-time bias. Stabilised inverse probability weighting addressed confounding by indication and censoring. The overall model was sex-stratified and adjusted for FIB-4, clinically significant portal hypertension (CSPH), type 2 diabetes mellitus (T2DM) and smoking. A prespecified T2DM-restricted analysis used T2DM-specific IPTW plus IPCW, sex stratification and CSPH adjustment. RESULTS: During follow-up, 50 patients developed HCC. Crude incidence was highest among patients with FIB-4 > 3.25, CSPH and T2DM without metformin exposure (4.84 cases per 100 person-years). In the overall weighted model, CME was associated with lower HCC risk (HR, 0.46 per year; 95% CI, 0.27-0.77; p = 0.004). CSPH, T2DM, smoking and FIB-4 > 3.25 independently increased risk. In the T2DM-restricted model, each additional year remained associated with lower HCC hazard (HR, 0.49; 95% CI, 0.29-0.84; p = 0.009), whereas CSPH was associated with higher risk (HR, 6.04; 95% CI, 2.12-17.19; p < 0.001). CONCLUSION: After SVR, CME was associated with lower HCC risk; this possible duration-dependent inverse association was clinically interpretable only among metformin-eligible patients with T2DM.